The applicants have been investigating associations between clinical depression and immunity. This research, which has been supported by the NIMH Small Grants Program, 1 R03 MH 37774-01MSMB, demonstrated that responses to T cell and T-dependent B cell mitogens as well as the absolute number of lymphocytes and T and B cells were significantly lower in drug free hospitalized patients with major depressive disorder than in apparently healthy matched controls. We also found that a group of less severely depressed outpatients with major depressive disorder had no changes in mitogen responses but did have a decrease in the number of lymphocytes and that hospitalized schizophrenics did not differ from matched controls on any of the immune measures. These findings suggest that depression is associated with altered immune function. The proposed research will investigate whether altered immunity is specific to the state of being depressed and if it is related to severity of the illness. Immune function will therefore be assessed in drug free patients with mild and severe depressive disorders compared with matched controls during depression and in clinical remission. Studies of alterations of immunity in depression may provide information about underlying neurobiological processes in depressive states. The immune changes may be related to other biological systems which can influence the lymphocyte and other immunocompetent and immunoregulatory cells. Neuroendocrine function and specifically cortisol secretion will therefore be investigated in relation to altered immunity in depressed patients. To further elucidate the biological processes which may link depression and the immune system, a comprehensive investigation of immunity will be undertaken, including: antigen as well as mitogen responses, T-independent B cell mitogen responses, numbers of T, T helper, T suppressor and B lymphocytes, natural killer cell function, and phagocyte activity. These studies may help to elucidate the pathophysiology of depressive states manifested in patterns of dysregulation of neurotransmitter, neuroendocrine and immune systems. The investigation of specific alterations in the immune system of depressives and their behavioral and neurobiological correlates may also provide a biologic basis for precise diagnosis of affective diseases as well as of risk factors. The findings may ultimately suggest strategies for intervention and treatment of depression.